Color vision depends upon the differential expression in retinal cone photoreceptors of opsin photopigments that confer sensitivity to different regions of the visible light spectrum. Most mammalian species are dichromatic and express opsins for sensitivity to medium-longer (M, green) or short (S, blue) wavelengths of light. Humans share this system but have trichromatic function because of a gene duplication that created another opsin gene for sensitivity to long wave (L, red) light. The mechanisms that differentially pattern opsins are critically important for color vision. However, the underlying signals and genetic controls have remained largely elusive. Our study of the Thrb thyroid hormone receptor gene identified an unexpectedly critical role for a thyroid hormone receptor, TRb2, in the diversification of M and S opsin expression in sub-populations of cones in a mouse model. Deletion of TRb2 results in a loss of M opsin, revealing a key role for TRb2 in opsin patterning. The unexpected nature of this finding raises questions regarding the link between the endocrine and visual systems. Previously, in the study of thyroid disorders in humans or in mammalian model species, the possibility of color visual deficiencies had been largely overlooked. The project aims to investigate how TRb2 and thyroid hormone regulate cone development and to investigate which genes may cooperate with Thrb in the color visual system. Progress: 1. Thyroid hormone administration was found to modify the timing and pattern of opsin expression in neonatal cone development in a mouse model, supporting the hypothesis that the hormonal ligand is important in modifying TRb2 activity in cone development. Additional studies are testing the consequences of a lack of thyroid hormone at sensitive, early stages of retinal development. These studies would indicate opsin abnormalities or other cone defects that may potentially arise in developmental thyroid disorders. 2. Candidate genes that may cooperate with the Thrb gene in the development of cone photoreceptors include those encoding deiodinase enzymes that could activate or inactivate thyroid hormone in the retinal target tissues at key stages in development. The findings suggest the multigenic nature of the controls that direct the development of cone photoreceptors and the function of the color visual system. Ongoing studies have identified deiodinase expression in the neural retina at embryonic and neonatal stages. Type 3 deiodinase, a thyroid hormone-inactivating enzyme, was found to be expressed in the immature neural retina. Studies in genetic models suggest type 3 deiodinase is critical for limiting the exposure of immature cones to thyroid hormone at sensitive periods of development. The results indicate the developmental importance of mechanisms that both augment as well as constrain thyroid hormone action on specific cell types in immature tissues.